US2025360194A1PendingUtilityA1

Herpes simplex virus mrna vaccines

59
Assignee: MODERNATX INCPriority: Dec 8, 2021Filed: Dec 7, 2022Published: Nov 27, 2025
Est. expiryDec 8, 2041(~15.4 yrs left)· nominal 20-yr term from priority
Inventors:Kapil BahlAndrea CarfiSumana ChandramouliAnthony DipiazzaAlec FreynKai WuYen-Ting Lai
C07K 14/005A61K 2039/70A61K 2039/57A61K 2039/53A61P 31/22A61K 2039/545A61K 2039/55555C12N 2710/16622C12N 2710/16634A61K 39/12
59
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Claims

Abstract

Provided herein are messenger ribonucleic acid (mRNA) vaccines encoding multiple herpes simplex virus (HSV) antigens involved in viral attachment and entry. Also provided are methods of using the vaccines and compositions comprising the vaccines.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A herpes simplex virus (HSV) messenger ribonucleic acid (mRNA) vaccine comprising
 (a) an mRNA comprising an open reading frame encoding an HSV glycoprotein B (gB) that comprises a truncated C-terminus, relative to a wild-type HSV gB;   (b) an mRNA comprising an open reading frame encoding an HSV glycoprotein C (gC);   (c) an mRNA comprising an open reading frame encoding an HSV glycoprotein D (gD);   (d) an mRNA comprising an open reading frame encoding an HSV intracellular protein 0 (ICP0);   (e) an mRNA comprising an open reading frame encoding an HSV intracellular protein 4 (ICP4); and   (f) a lipid nanoparticle.   
     
     
         2 . The HSV mRNA vaccine of  claim 1 , wherein the HSV gB comprises a truncated cytoplasmic tail. 
     
     
         3 . The HSV mRNA vaccine of  claim 1 , wherein the HSV gB does not comprise a cytoplasmic tail. 
     
     
         4 . The HSV mRNA vaccine of any one of  claims 1-3 , wherein the HSV gC comprises an F327A substitution and a truncated C-terminus, relative to a wild-type HSV gC. 
     
     
         5 . The HSV mRNA vaccine of  claim 4 , wherein the HSV gC comprises a truncated cytoplasmic tail. 
     
     
         6 . The HSV mRNA vaccine of  claim 4 , wherein the HSV gB and/or HSV gC does not comprise a cytoplasmic tail. 
     
     
         7 . The HSV mRNA vaccine of any one of  claims 1-6 , wherein the HSV ICP0 lacks a nuclear localization signal and/or a RING finger domain. 
     
     
         8 . The HSV mRNA vaccine of any one of  claims 1-7 , wherein the HSV ICP0 comprises a higher density of CD8+ T cell epitopes, relative to a wild-type HSV ICP0. 
     
     
         9 . The HSV mRNA vaccine of any one of  claims 1-8 , wherein the HSV ICP4 lacks a nuclear localization signal and/or a RING finger domain. 
     
     
         10 . The HSV mRNA vaccine of any one of  claims 1-9 , wherein the HSV ICP4 comprises a higher density of CD8+ T cell epitopes, relative to a wild-type HSV ICP4. 
     
     
         11 . A herpes simplex virus (HSV) messenger ribonucleic acid (mRNA) vaccine comprising
 (a) an mRNA comprising an open reading frame encoding an HSV glycoprotein B (gB), optionally wherein the gB comprises a truncated C-terminus, relative to a wild-type HSV gB;   (b) an mRNA comprising an open reading frame encoding a HSV glycoprotein C (gC) that comprises an F327A substitution, and a truncated C-terminus, relative to a wild-type HSV gC; and   (c) an mRNA comprising an open reading frame encoding a wild-type HSV glycoprotein D (gD);   (d) a lipid nanoparticle.   
     
     
         12 . The HSV mRNA vaccine of  claim 11  further comprising an mRNA comprising an open reading frame encoding a HSV intracellular protein 0 (ICP0) comprising a higher density of CD8+ T cell epitopes relative to a wild-type HSV ICP0. 
     
     
         13 . The HSV mRNA vaccine of  claim 11 or 12 , further comprising an mRNA comprising an open reading frame encoding a HSV intracellular protein 4 (ICP4) comprising a higher density of CD8+ T cell epitopes relative to a wild-type HSV ICP4. 
     
     
         14 . The HSV mRNA vaccine of any one of  claims 11-13 , wherein the HSV gB and/or HSV gC comprises a truncated cytoplasmic tail. 
     
     
         15 . The HSV mRNA vaccine of any one of  claims 11-13 , wherein the HSV gB and/or HSV gC does not comprise a cytoplasmic tail. 
     
     
         16 . A herpes simplex virus (HSV) messenger ribonucleic acid (mRNA) vaccine comprising
 (a) an mRNA comprising an open reading frame encoding a HSV glycoprotein C (gC) that comprises an F327A substitution, and a truncated C-terminus, relative to a wild-type HSV gC;   (b) an mRNA comprising an open reading frame encoding a wild-type HSV glycoprotein D (gD);   (c) an mRNA comprising an open reading frame encoding a HSV intracellular protein 0 (ICP0) comprising a higher density of CD8+ T cell epitopes relative to a wild-type HSV ICP0;   (d) an mRNA comprising an open reading frame encoding a HSV intracellular protein 4 (ICP4) comprising a higher density of CD8+ T cell epitopes relative to a wild-type HSV ICP4; and   (e) a lipid nanoparticle.   
     
     
         17 . The HSV mRNA vaccine of  claim 16 , wherein the HSV gC comprises a truncated cytoplasmic tail. 
     
     
         18 . The HSV mRNA vaccine of  claim 16 or 17 , wherein the HSV gC does not comprise a cytoplasmic tail. 
     
     
         19 . The HSV vaccine of  any one of the preceding claims , wherein the vaccine induces a Th1-polarized CD4+ T cell-mediated immune response to the HSV gC, gB, and/or gD. 
     
     
         20 . The HSV vaccine of  any one of the preceding claims , wherein the vaccine elicits more Th1 cells that are specific to an antigen selected from HSV gB, gC, or gD, than Th2 cells specific to the antigen. 
     
     
         21 . The HSV vaccine of  any one of the preceding claims , wherein a population of CD4+ T cells specific to an antigen selected from HSV gB, gC, or gD, comprises more than 50% Th1 cells. 
     
     
         22 . The HSV vaccine of  any one of the preceding claims , wherein each of the HSV gB, gC, and gD comprises a transmembrane domain. 
     
     
         23 . The HSV vaccine of  any one of the preceding claims , wherein:
 (a) the HSV gB has a length of about 798 amino acids;   (b) the HSV gC has a length of about 469 amino acids;   (c) the HSV ICP0 comprises a truncation in a nuclear localization signal, RING finger domain, and/or USP7-binding domain relative to a wild-type HSV ICP0; and/or   (d) the HSV ICP4 comprises a truncation in a nuclear localization signal and/or DNA-binding domain relative to a wild-type HSV ICP4.   
     
     
         24 . The HSV vaccine of  claim 23 , wherein the HSV ICP0 does not comprise a nuclear localization signal, does not comprise a USP7-binding domain, and/or does not comprise a RING finger domain. 
     
     
         25 . The HSV vaccine of  claim 23 or 24 , wherein the HSV ICP0 does not comprise a nuclear localization signal and/or comprises a truncated DNA-binding domain. 
     
     
         26 . The HSV vaccine of  any one of the preceding claims , wherein:
 (a) the HSV gB comprises an amino acid sequence having at least 90%, at least 95%, or 100% identity to the amino acid sequence of SEQ ID NO: 54;   (b) the HSV gC comprises an amino acid sequence having at least 90%, at least 95%, or 100% identity to the amino acid sequence of SEQ ID NO: 63;   (c) the HSV gD comprises an amino acid sequence having at least 90%, at least 95%, or 100% identity to the amino acid sequence of SEQ ID NO: 39;   (d) the HSV ICP0 comprises an amino acid sequence having at least 90%, at least 95%, or 100% identity to the amino acid sequence of SEQ ID NO: 47; and/or   (e) the HSV ICP4 comprises an amino acid sequence having at least 90%, at least 95%, or 100% identity to the amino acid sequence of SEQ ID NO: 49.   
     
     
         27 . The HSV vaccine of  any one of the preceding claims , wherein the molar ratio of mRNA of (c) and (d) to the mRNA of (a), (b), and (c) is no more than 0.8:1. 
     
     
         28 . The HSV vaccine of  any one of the preceding claims , wherein the one or more mRNAs comprise a chemical modification. 
     
     
         29 . The HSV vaccine of  any one of the preceding claims , wherein 100% of the uracil nucleotides of the one or more mRNAs comprise a chemical modification. 
     
     
         30 . The HSV vaccine of  claim 28 or 29 , wherein the chemical modification is 1-methylpseudouracil. 
     
     
         31 . The HSV vaccine of  any one of the preceding claims , wherein the lipid nanoparticle comprises an ionizable lipid, a neutral lipid, a sterol, and a PEG-modified lipid. 
     
     
         32 . The HSV vaccine of  claim 31 , wherein the lipid nanoparticle comprises 40-50 mol % ionizable lipid, 5-15 mol % neutral lipid, 30-50 mol % sterol, and 0.5-3 mol % PEG-modified lipid. 
     
     
         33 . The HSV vaccine of  claim 31 or 32 , wherein:
 the ionizable lipid comprises a structure of Compound (I):   
       
         
           
           
               
               
           
         
         the neutral lipid is distearoylphosphatidylcholine (DSPC); 
         the sterol is cholesterol; and/or 
         the PEG-modified lipid is 1,2 dimyristoyl-sn-glycerol, methoxypolyethyleneglycol (PEG-DMG). 
       
     
     
         34 . A method comprising administering to a subject the vaccine of  any one of the preceding claims . 
     
     
         35 . The method of  claim 34 , wherein the subject has an HSV infection or has been exposed to HSV. 
     
     
         36 . The method of  claim 34 or 35 , wherein the vaccine is administered in an amount effective for preventing a latent or active HSV infection in the subject. 
     
     
         37 . The method of  any one of the preceding claims , wherein the vaccine is administered in an amount effective for preventing reactivation of a latent HSV infection in the subject, for preventing replication of HSV, reducing duration of an HSV infection in the subject, for reducing a number of replication-competent HSV particles in the subject, and/or for reducing a number of cells in the subject that comprise an HSV genome. 
     
     
         38 . The method of  any one of the preceding claims , wherein the vaccine induces a CD4+ T cell-mediated immune response to the HSV gB, gC, and/or gD, and the CD4+ T cells bind to one or more CD4+ T cell epitopes of the HSV gB, gC, or gD. 
     
     
         39 . The method of  claim 38 , wherein at least 50% of the CD4+ T cells produce one or more cytokines selected from the group consisting of IFN-γ, IL-2, and TNF-α. 
     
     
         40 . The method of  claim 38 or 39 , wherein fewer than 10% of the CD4+ T cells produce any one or more of IL-4, IL-5, IL-9, IL-10, or IL-13. 
     
     
         41 . The method of  any one of the preceding claims , wherein the vaccine induces a CD8+ T cell-mediated immune response to the HSV ICP0 and/or or ICP4, and the CD8+ T cells bind to one or more CD8+ T cell epitopes of the HSV ICP0 and or ICP4. 
     
     
         42 . The method of  claim 41 , wherein the CD8+ T cells are cytotoxic. 
     
     
         43 . A modified herpes simplex virus (HSV) intracellular protein 0 (ICP0) comprising fewer amino acids than a wild-type HSV ICP0. 
     
     
         44 . The modified HSV ICP0 of  claim 43 , wherein the modified HSV ICP0 comprises a truncation in a nuclear localization signal relative to a wild-type HSV ICP0. 
     
     
         45 . The modified HSV ICP0 of  claim 43 , wherein the modified HSV ICP0 does not comprise a nuclear localization signal. 
     
     
         46 . The modified HSV ICP0 of any one of  claims 43-45 , wherein the modified HSV ICP0 comprises a truncation in a RING finger domain relative to a wild-type HSV ICP0. 
     
     
         47 . The modified HSV ICP0 of any one of  claims 43-45 , wherein the modified HSV ICP0 does not comprise a RING finger domain. 
     
     
         48 . The modified HSV ICP0 of any one of  claims 43-47 , wherein the modified HSV ICP0 comprises a truncation in a USP7-binding domain relative to the wild-type HSV ICP0. 
     
     
         49 . The modified HSV ICP0 of any one of  claims 43-47 , wherein the modified HSV ICP0 does not comprise a USP7-binding domain. 
     
     
         50 . The modified HSV ICP0 of any one of  claims 43-49 , wherein the modified HSV ICP0 comprises a linker between a first portion of the modified HSV ICP0 and a second portion of the modified HSV ICP0. 
     
     
         51 . The modified HSV ICP0 of  claim 50 , wherein the linker comprises 2-10 glycine residues. 
     
     
         52 . The modified HSV ICP0 of any one of  claims 43-51 , wherein the modified HSV ICP0 comprises an amino acid sequence having a length that is no more than 65% the length of the wild-type HSV IPC0. 
     
     
         53 . The modified HSV ICP0 of any one of  claims 43-52 , wherein the modified HSV ICP0 amino acid sequence comprises at least 65% as many T cell epitopes as the wild-type HSV ICP0. 
     
     
         54 . The modified HSV ICP0 of any one of  claims 43-53 , wherein the modified HSV ICP0 comprises about 487 amino acids. 
     
     
         55 . A ribonucleic acid (RNA) comprising an open reading frame encoding the modified HSV ICP0 of any one of  claims 43-54 . 
     
     
         56 . A modified herpes simplex virus (HSV) intracellular protein 4 (ICP4) comprising fewer amino acids than a wild-type HSV ICP4. 
     
     
         57 . The modified HSV ICP4 of  claim 56 , wherein the modified HSV ICP4 comprises a truncation in a nuclear localization signal relative to the wild-type HSV ICP4. 
     
     
         58 . The modified HSV ICP4 of  claim 56 , wherein the modified HSV ICP4 does not comprise a nuclear localization signal. 
     
     
         59 . The modified HSV ICP4 of any one of  claims 56-58 , wherein the modified HSV ICP4 comprises a truncation in a DNA-binding domain relative to the wild-type HSV ICP4. 
     
     
         60 . The modified HSV ICP4 of  claim 59 , wherein the modified HSV ICP4 does not comprise a DNA-binding domain. 
     
     
         61 . The modified HSV ICP4 of any one of  claims 56-60 , wherein the modified HSV ICP4 comprises a linker between a first portion of the modified HSV ICP4 and a second portion of the modified HSV ICP4. 
     
     
         62 . The modified HSV ICP4 of  claim 61 , wherein the linker comprises 2-10 glycine residues. 
     
     
         63 . The modified HSV ICP4 of any one of  claims 56-62 , wherein the modified HSV ICP4 comprises an amino acid sequence having a length that is no more than 65% the length of the wild-type HSV IPC4. 
     
     
         64 . The modified HSV ICP4 of any one of  claims 56-63 , wherein the modified HSV ICP4 amino acid sequence comprises at least 65% as many T cell epitopes as the wild-type HSV ICP4. 
     
     
         65 . The modified HSV ICP4 of any one of  claims 56-64 , wherein the modified HSV ICP4 comprises about 687 amino acids. 
     
     
         66 . A ribonucleic acid (RNA) comprising an open reading frame encoding the modified HSV ICP4 of any one of  claims 56-65 . 
     
     
         67 . A herpes simplex virus (HSV) protein comprising an amino acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of any one of SEQ ID NOs: 54, 63, 47, and 49. 
     
     
         68 . A messenger ribonucleic acid (mRNA) comprising an open reading frame encoding the HSV protein of  claim 67 . 
     
     
         69 . A messenger ribonucleic acid (mRNA) comprising an open reading frame comprising a nucleic acid sequence having at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the nucleic acid sequence of any one of SEQ ID NOs: 19, 28, 4, 12, and 14. 
     
     
         70 . The mRNA of  claim 68 or 69 , wherein the mRNA comprises a chemical modification. 
     
     
         71 . The mRNA of any one of  claims 68-70 , wherein 100% of the uracil nucleotides of the mRNA comprises a chemical modification. 
     
     
         72 . The mRNA of  claim 71 , wherein the chemical modification is 1-methylpseudouracil.

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